WO2021198040A1 - Procédé de préparation de 3'-o-amino-2'-deoxyribonucleoside-5'-triphosphates - Google Patents

Procédé de préparation de 3'-o-amino-2'-deoxyribonucleoside-5'-triphosphates Download PDF

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Publication number
WO2021198040A1
WO2021198040A1 PCT/EP2021/057835 EP2021057835W WO2021198040A1 WO 2021198040 A1 WO2021198040 A1 WO 2021198040A1 EP 2021057835 W EP2021057835 W EP 2021057835W WO 2021198040 A1 WO2021198040 A1 WO 2021198040A1
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WO
WIPO (PCT)
Prior art keywords
hydroxylamine
aryl
oxyamine
triphosphate
deoxyribonucleoside
Prior art date
Application number
PCT/EP2021/057835
Other languages
English (en)
Inventor
Filip Wojciechowski
Thomas YBERT
Original Assignee
Dna Script
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dna Script filed Critical Dna Script
Priority to IL296814A priority Critical patent/IL296814A/en
Priority to EP21713979.9A priority patent/EP4126895A1/fr
Priority to CA3172698A priority patent/CA3172698A1/fr
Priority to KR1020227037544A priority patent/KR20220160076A/ko
Priority to CN202180026121.1A priority patent/CN115362161A/zh
Priority to JP2022559341A priority patent/JP7554279B2/ja
Priority to AU2021246815A priority patent/AU2021246815B2/en
Publication of WO2021198040A1 publication Critical patent/WO2021198040A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/02—Phosphorylation
    • C07H1/04—Introducing polyphosphoric acid radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to methods for preparing 3 ’-O- amino-2 ’- deoxyribonucleoside-5 ’ -triphosphates with reduced 3 ’ -hydroxy-2’ -deoxyribonucleoside-5 ’ - triphosphate contamination.
  • the invention also includes compositions made by methods of the invention.
  • such methods of the invention comprise the following steps: (a) protecting 5’ -hydroxy group of a 2’ -deoxyribonucleoside; (b) converting (S)-3’ -hydroxy group of the compound obtained in step (a) into (R)-3’ -hydroxy group; (c) reacting the product of step (b) with an N -hydroxyphthalimide to produce a 5 ’ -O-protected-3 ’ -O-phthalimido-2’ - deoxynucleoside; (d) deprotecting the 5’ -hydroxy group of the product of step (c); (e) converting the product of step (d) to a 3 ’-0-(N-acetone-oxime)-2’ -deoxynucleoside; (f) triphosphorylating 5 ’-hydroxy group of the product of step (e) to give a 3’-0-(N-acetone- oxime)-2’ -deoxynucleoside triphosphate; and (
  • compositions comprise an aqueous solution containing a 3 ’ -O-amino-2’ -deoxyribonucleoside-5 ’ -triphosphate and an aryl-oxyamine at a concentration of less than 2% by volume.
  • Fig. 1 illustrates the conventional synthesis scheme for making 3’-0-amine-2’- deoxynucleoside triphosphate monomer.
  • Fig. 2 illustrates an embodiment of the invention for converting, or deprotecting, a 3 ’ -acetone-oxime -nucleoside-triphosphate to a 3 ’ -ONH2 -nucleoside triphosphate using benzylhydroxylamine .
  • Fig. 3 A is a chromatogram of a crude reaction product described in Example 1.
  • Fig. 3B is a chromatogram of the desired 3 ’ -O-amino-2’ -deoxyguanosine-5 ’ - triphosphate product of Example 1.
  • Fig.4 illustrates examples of bases for 3 ’ -O-amino-2’ -deoxyribonucleoside-5 ’ - triphosphate, according to the invention, wherein Z is a G carbon of a 2’ -deoxyribose-5 ’ - triphosphate, R is either H, C3 ⁇ 4, or a linking group, and X is either N or C-R.
  • the present invention relates to a method for preparing 3’ -O-amino-2 ’- deoxyribonucleoside-5 ’ -triphosphates using the general steps of:
  • step (c) reacting the product of step (b) with an N -hydroxy phthalimide to produce a 5’-0- protected-3 ’ -O-phthalimido-2’ -deoxynucleoside ;
  • step (e) converting the product of step (d) to a 3 ’ -0-(N- acetone-oxime)-2 ’ -deoxynucleoside ;
  • step (f) triphosphorylating 5 ’-hydroxy group of the product of step (e) to give a 3’-0-(N- acetone-oxime)-2 ’ -deoxynucleoside triphosphate;
  • step (g) converting the product of step (f) to a 3 ’ -O-amine-2’ -deoxynucleoside triphosphate.
  • the 2' -deoxynucleosides of adenine, guanine, cytosine, thymine and uracil are respectively 2' -deoxyadenosine, 2' -deoxyguanosine, 2' -deoxycytidine, 2' -deoxythymidine and 2' -deoxyuridine.
  • the 3 ’ -0-(N-acetone-oxime)-2 ’ -deoxynucleoside triphosphate of step (f) is converted to a 3 ’ -O-amine-2 ’ -deoxynucleoside triphosphate by treating with an aryl-oxyamine, as illustrated in Fig 2.
  • the aryl- oxyamine is an unsubstituted or substituted O-benzylhydroxylamine or a substituted or unsubstituted phenylhydroxylamine.
  • substituents include methoxy, nitro, halo, wherein in particular halo is fluoro, chloro or bromo.
  • Exemplary substituted O- benzylhydroxylamines include, but are not limited to, 0-(2,3,4,5,6- Pentafluorobenzyl)hydroxylamine, and 0-(4-Nitrobenzyl)hydroxylamine.
  • the aryl-oxyamine used with the method of the invention is O- benzylhydroxy lamine .
  • the aryl-oxyamine used with the method of the invention is a substituted or unsubstituted phenylhydroxylamine.
  • exemplary substituents include methoxy, nitro, halo, wherein in particular halo is fluoro, chloro or bromo.
  • the conversion step (g) may be performed using an aqueous solution of an aryl-oxyamine.
  • pyrimidine 3 ’ -0-(N-acetone-oxime)-2 ’ -deoxynucleoside triphosphates are converted or deprotected to form 3 ’ -O-amine-2’ -deoxynucleoside triphosphates at a pH between 6.8 and 7.0.
  • purine 3’-0-(N-acetone-oxime)-2’- deoxynucleoside triphosphates are converted or deprotected to form 3’ -O-amine-2’ - deoxynucleoside triphosphates at a pH between 6.0 and 6.8.
  • a concentration of aryl-oxyamine is used which is high enough to bring about the conversion but low enough not to require purification of 3 ’ -O-amine-2’ -deoxynucleoside triphosphates prior to use in polynucleotide synthesis.
  • concentration of aryl-oxyamine is in the range of from 1 to 100 percent (v/v). In some embodiment, such concentration of aryl-oxyamine is in the range of from 1 to 2 percent (v/v).
  • such concentration of aryl-oxyamine is less than 2 percent (v/v). In other embodiments, such concentration of aryl-oxyamine is less than 1 percent (v/v).
  • aryl-oxyamines used in the method of the invention include substituted or unsubstituted O-benzylhydroxylamine, substituted or unsubstituted O- phenylhydroxylamine, substituted or unsubstituted O-phenylethyldydroxylamine, substituted or unsubstituted O-benzyloxyethylhydroxylamine, and substituted or unsubstituted O- phenoxyethylhyroxylamines, wherein the substituents are selected from halo, methoxy, nitro.
  • halo is fluoro, chloro or bromo.
  • aryl-oxyamines used in the method of the invention include, but are not limited to, O-benzylhydroxylamine,
  • Nitrobenzyl)hydroxylamine 0-(4 ⁇ Methoxybenzyl)hydroxylamine, 0-[(3,4-
  • Bromophenyl)hydroxylamine 0-[2-(Trifluoromethyl)phenyl]hydroxylamine, or 0-(2- Phenoxyethyl)hydroxylamine.
  • composition comprising an aqueous solution containing a 3 ’ -O-amino-2’ -deoxyribonucleoside-5 ’ -triphosphate and an aryl-oxyamine at a concentration of less than 2% by volume.
  • said aryl-oxyamine is O-benzylhydroxylamine or O-phenylhydroxylamine.
  • said 3’-0- amino-2’ -deoxyribonucleoside-5 ’ -triphosphate may have a base selected from the group consisting of adenine, thymine, guanine, cytosine, uracil, inosine, xanthine or hypoxanthine.
  • 3 ’ -O-amino-2 ’ -deoxyribonucleoside-5 ’ -triphosphate has a base selected from the group consisting of base illustrated Figure 4.
  • the linking group is alkyl linkers, alkenyl linkers, thioether linkers, aminoalkyl, aminoallyl, azidealkyl, azideallyl propargylamine, bis-propargyl, or bis-propargyl-PEG.
  • Example 1 Deprotection of purine nucleobases (A, G)3 ’ -O- Amino-2 ’ -deoxyguanosine-5 ’ - triphosphate
  • the aqueous composition of 3’-ONH2- nucleoside triphosphates may contain a low amount of O-benzylhydroxylamine, sodium acetate and sodium chloride.
  • Fig. 3B is an HPLC chromatogram of the 3 ’-O- Amino-2’ - deoxyguanosine-5 ’ -triphosphate product.
  • the liquid-liquid extraction solvent in the examples is diethyl ether, but can be any organic solvent such as methyl tert-butyl ether, dichloromethane, toluene, pentane etc. and mixtures thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Saccharide Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de 3'-O-amino-2'-deoxyribonucleoside- 5'-triphosphates présentant une contamination réduite en 3'-hydroxy-2'-deoxyribonucleoside-5'-triphosphate par conversion de 3'-(N-acetone-oxime)-2'-deoxynucleoside triphosphate en 3'-O- amine-2'-deoxynucleoside triphosphate par traitement avec une aryle-oxyamine.
PCT/EP2021/057835 2020-03-30 2021-03-25 Procédé de préparation de 3'-o-amino-2'-deoxyribonucleoside-5'-triphosphates WO2021198040A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
IL296814A IL296814A (en) 2020-03-30 2021-03-25 Method for preparing 3'-o-amino-2'-deoxyribonucleoside-5'-triphosphates
EP21713979.9A EP4126895A1 (fr) 2020-03-30 2021-03-25 Procédé de préparation de 3'-o-amino-2'-deoxyribonucleoside-5'-triphosphates
CA3172698A CA3172698A1 (fr) 2020-03-30 2021-03-25 Procede de preparation de 3'-o-amino-2'-deoxyribonucleoside-5'-triphosphates
KR1020227037544A KR20220160076A (ko) 2020-03-30 2021-03-25 3'-o-아미노-2'-데옥시리보뉴클레오사이드-5'-트라이포스페이트의 제조 방법
CN202180026121.1A CN115362161A (zh) 2020-03-30 2021-03-25 用于制备3’-o-氨基-2’-脱氧核糖核苷-5’-三磷酸的方法
JP2022559341A JP7554279B2 (ja) 2020-03-30 2021-03-25 ３’－ｏ－アミノ－２’－デオキシリボヌクレオシド－５’－三リン酸を調製する方法
AU2021246815A AU2021246815B2 (en) 2020-03-30 2021-03-25 Method for preparing 3'-O-amino-2'-deoxyribonucleoside-5'-triphosphates.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20166719 2020-03-30
EP20166719.3 2020-03-30

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WO2021198040A1 true WO2021198040A1 (fr) 2021-10-07

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US (1) US11661436B2 (fr)
EP (1) EP4126895A1 (fr)
JP (1) JP7554279B2 (fr)
KR (1) KR20220160076A (fr)
CN (1) CN115362161A (fr)
AU (1) AU2021246815B2 (fr)
CA (1) CA3172698A1 (fr)
IL (1) IL296814A (fr)
WO (1) WO2021198040A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4265628A3 (fr) * 2019-09-10 2024-01-03 Pacific Biosciences of California, Inc. Modification reversible de nucleotides

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117143942A (zh) * 2023-10-30 2023-12-01 泰兴合全药业有限公司 3’-氨基-2’,3’-双脱氧鸟苷5’-三磷酸的合成方法

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EP0381335A1 (fr) 1989-01-31 1990-08-08 Tanabe Seiyaku Co., Ltd. Agent antiviral et nucléoside
US7544794B1 (en) 2005-03-11 2009-06-09 Steven Albert Benner Method for sequencing DNA and RNA by synthesis
WO2010110775A1 (fr) * 2009-03-23 2010-09-30 Steven Albert Benner Réactifs utilisés pour l'interruption réversible d'extension d'amorce
US8034923B1 (en) 2009-03-27 2011-10-11 Steven Albert Benner Reagents for reversibly terminating primer extension
US20180265537A1 (en) * 2017-03-16 2018-09-20 Steven A. Benner Nucleoside Triphosphates with Stable Aminoxy Groups
WO2019097233A1 (fr) * 2017-11-14 2019-05-23 Nuclera Nucleics Ltd Dérivés nucléotidiques contenant des fractions masquées d'amine et leur utilisation dans le cadre d'une synthèse enzymatique d'acides nucléiques avec et sans gabarit
WO2020043846A1 (fr) 2018-08-31 2020-03-05 Dna Script Procédé de préparation de 3'-o-amino-2'-déoxyribonucléoside-5'-triphosphate

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Publication number Priority date Publication date Assignee Title
EP4028407B1 (fr) * 2019-09-10 2023-08-16 Pacific Biosciences of California, Inc. Modification reversible de nucleotides

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EP0381335A1 (fr) 1989-01-31 1990-08-08 Tanabe Seiyaku Co., Ltd. Agent antiviral et nucléoside
US7544794B1 (en) 2005-03-11 2009-06-09 Steven Albert Benner Method for sequencing DNA and RNA by synthesis
US8212020B2 (en) 2005-03-11 2012-07-03 Steven Albert Benner Reagents for reversibly terminating primer extension
WO2010110775A1 (fr) * 2009-03-23 2010-09-30 Steven Albert Benner Réactifs utilisés pour l'interruption réversible d'extension d'amorce
US8034923B1 (en) 2009-03-27 2011-10-11 Steven Albert Benner Reagents for reversibly terminating primer extension
US20180265537A1 (en) * 2017-03-16 2018-09-20 Steven A. Benner Nucleoside Triphosphates with Stable Aminoxy Groups
US10472383B2 (en) 2017-03-16 2019-11-12 Steven A Benner Nucleoside triphosphates with stable aminoxy groups
WO2019097233A1 (fr) * 2017-11-14 2019-05-23 Nuclera Nucleics Ltd Dérivés nucléotidiques contenant des fractions masquées d'amine et leur utilisation dans le cadre d'une synthèse enzymatique d'acides nucléiques avec et sans gabarit
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4265628A3 (fr) * 2019-09-10 2024-01-03 Pacific Biosciences of California, Inc. Modification reversible de nucleotides

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US20210300961A1 (en) 2021-09-30
AU2021246815A1 (en) 2022-10-27
JP7554279B2 (ja) 2024-09-19
CA3172698A1 (fr) 2021-10-07
JP2023519395A (ja) 2023-05-10
CN115362161A (zh) 2022-11-18
IL296814A (en) 2022-11-01
EP4126895A1 (fr) 2023-02-08
AU2021246815B2 (en) 2023-09-14
KR20220160076A (ko) 2022-12-05
US11661436B2 (en) 2023-05-30

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